Pub Date : 2024-11-11eCollection Date: 2024-12-12DOI: 10.1021/acsmedchemlett.4c00241
Michele Retini, Juulia Järvinen, Katayun Bahrami, Janne Tampio, Francesca Bartoccini, Petri Riihelä, Henna Pehkonen, Arina Värä, Tuomo Laitinen, Kristiina M Huttunen, Jarkko Rautio, Giovanni Piersanti, Juri M Timonen
This research investigates boronated tryptophans as potential boron delivery agents for boron neutron capture therapy (BNCT) of cancer. We synthesized both enantiomers of 5- and 6-boronotryptophans (1a and 1b) using simple and inexpensive methods. Their uptake was assessed in two human cancer cell lines, CAL27 (head and neck cancer) and U87-MG (brain cancer), and compared to l-p-boronophenylalanine (l-BPA) as a reference. To determine whether these tryptophan derivatives are substrates for large amino acid transporter 1, we performed molecular dynamics simulations to explore their transport mechanism. Our findings reveal differences in boron compound accumulation between the cancer cell lines, indicating that tryptophan derivatives could serve as effective boron carriers when the clinically used boron carrier, BPA, is ineffective.
{"title":"Asymmetric Synthesis and Biological Evaluation of Both Enantiomers of 5- and 6-Boronotryptophan as Potential Boron Delivery Agents for Boron Neutron Capture Therapy.","authors":"Michele Retini, Juulia Järvinen, Katayun Bahrami, Janne Tampio, Francesca Bartoccini, Petri Riihelä, Henna Pehkonen, Arina Värä, Tuomo Laitinen, Kristiina M Huttunen, Jarkko Rautio, Giovanni Piersanti, Juri M Timonen","doi":"10.1021/acsmedchemlett.4c00241","DOIUrl":"10.1021/acsmedchemlett.4c00241","url":null,"abstract":"<p><p>This research investigates boronated tryptophans as potential boron delivery agents for boron neutron capture therapy (BNCT) of cancer. We synthesized both enantiomers of 5- and 6-boronotryptophans (<b>1a</b> and <b>1b</b>) using simple and inexpensive methods. Their uptake was assessed in two human cancer cell lines, CAL27 (head and neck cancer) and U87-MG (brain cancer), and compared to l-<i>p</i>-boronophenylalanine (l-BPA) as a reference. To determine whether these tryptophan derivatives are substrates for large amino acid transporter 1, we performed molecular dynamics simulations to explore their transport mechanism. Our findings reveal differences in boron compound accumulation between the cancer cell lines, indicating that tryptophan derivatives could serve as effective boron carriers when the clinically used boron carrier, BPA, is ineffective.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2121-2128"},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11eCollection Date: 2024-12-12DOI: 10.1021/acsmedchemlett.4c00518
Robert B Kargbo
The rapid advances in cancer research have led to novel therapeutic approaches focusing on previously undruggable targets and immune evasion mechanisms. Recent innovations exemplify these cutting-edge strategies, particularly in KRAS-targeting therapies using PROTAC technology and immune modulation to address resistance in cancer cells. These developments present promising methods for degrading oncogenic proteins and enhancing immune system responses, potentially transforming the cancer treatment landscape. This Patent Highlight showcases these breakthroughs, emphasizing their significant potential to transform cancer therapy.
{"title":"Targeting Cancer: A New Era in Cancer Therapy through Immune Fitness Modulation and KRAS Degradation.","authors":"Robert B Kargbo","doi":"10.1021/acsmedchemlett.4c00518","DOIUrl":"10.1021/acsmedchemlett.4c00518","url":null,"abstract":"<p><p>The rapid advances in cancer research have led to novel therapeutic approaches focusing on previously undruggable targets and immune evasion mechanisms. Recent innovations exemplify these cutting-edge strategies, particularly in KRAS-targeting therapies using PROTAC technology and immune modulation to address resistance in cancer cells. These developments present promising methods for degrading oncogenic proteins and enhancing immune system responses, potentially transforming the cancer treatment landscape. This Patent Highlight showcases these breakthroughs, emphasizing their significant potential to transform cancer therapy.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2074-2076"},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1021/acsmedchemlett.4c0051910.1021/acsmedchemlett.4c00519
Robert B. Kargbo*,
Recent innovations in psychedelic research have led to the development of novel compounds designed to enhance the therapeutic potential of psilocin and related tryptamines. This Patent Highlight reviews three essential patents that focus on improving the stability, bioavailability, and efficacy of these compounds for treating mental health disorders such as depression, anxiety, and substance use disorders. The compounds─4-pivaloyloxy-N-methyltryptammonium chloride, alkyl quaternary ammonium tryptamines, and 4-pivaloyloxy-N-methyltryptammonium derivatives─represent significant advancements in the field of psychedelic-assisted therapy. These innovations offer new hope for more reliable and effective treatments, particularly in addressing the limitations associated with traditional psychedelics. The findings from preclinical studies support the potential of these compounds to play a vital role in the treatment of mental and neurological disorders.
{"title":"Advances in Psychedelic Therapeutics: Novel Prodrugs and Derivatives for Enhanced Mental Health Treatment","authors":"Robert B. Kargbo*, ","doi":"10.1021/acsmedchemlett.4c0051910.1021/acsmedchemlett.4c00519","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00519https://doi.org/10.1021/acsmedchemlett.4c00519","url":null,"abstract":"<p >Recent innovations in psychedelic research have led to the development of novel compounds designed to enhance the therapeutic potential of psilocin and related tryptamines. This Patent Highlight reviews three essential patents that focus on improving the stability, bioavailability, and efficacy of these compounds for treating mental health disorders such as depression, anxiety, and substance use disorders. The compounds─4-pivaloyloxy-<i>N</i>-methyltryptammonium chloride, alkyl quaternary ammonium tryptamines, and 4-pivaloyloxy-<i>N</i>-methyltryptammonium derivatives─represent significant advancements in the field of psychedelic-assisted therapy. These innovations offer new hope for more reliable and effective treatments, particularly in addressing the limitations associated with traditional psychedelics. The findings from preclinical studies support the potential of these compounds to play a vital role in the treatment of mental and neurological disorders.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2071–2073 2071–2073"},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1021/acsmedchemlett.4c0038010.1021/acsmedchemlett.4c00380
Luigi Cutarella, Mattia Mori* and Claudiu T. Supuran,
Several antiepileptic drugs (AEDs) have been found to inhibit human carbonic anhydrases (hCAs), paving the way for repurposing AEDs for the treatment of various diseases, including cancer. Here, the hCAs inhibitory effects of levetiracetam, a highly prescribed AED that does not bear a common zinc-binding group, were investigated in vitro and in silico. Levetiracetam inhibited all tested hCAs, although with a specific profile compared to the reference acetazolamide, with remarkable efficacy against tumor-associated hCA IX and XII. Molecular docking and dynamics (MD) simulations emphasized H-bonding to the Zn(II)-coordinated water as a major anchor point for hCAs, as well as a persistent interaction within the catalytic site of hCA isoforms IX and XII compared to II, which correlates with experimental data. Our results may explain why levetiracetam is also clinically effective as an antitumor agent in patients developing epilepsy as a consequence of brain tumors.
{"title":"The Antiepileptic Drug Levetiracetam Inhibits Carbonic Anhydrase: In Vitro and In Silico Studies on Catalytically Active Human Isoforms","authors":"Luigi Cutarella, Mattia Mori* and Claudiu T. Supuran, ","doi":"10.1021/acsmedchemlett.4c0038010.1021/acsmedchemlett.4c00380","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00380https://doi.org/10.1021/acsmedchemlett.4c00380","url":null,"abstract":"<p >Several antiepileptic drugs (AEDs) have been found to inhibit human carbonic anhydrases (hCAs), paving the way for repurposing AEDs for the treatment of various diseases, including cancer. Here, the hCAs inhibitory effects of levetiracetam, a highly prescribed AED that does not bear a common zinc-binding group, were investigated <i>in vitro</i> and <i>in silico</i>. Levetiracetam inhibited all tested hCAs, although with a specific profile compared to the reference acetazolamide, with remarkable efficacy against tumor-associated hCA IX and XII. Molecular docking and dynamics (MD) simulations emphasized H-bonding to the Zn(II)-coordinated water as a major anchor point for hCAs, as well as a persistent interaction within the catalytic site of hCA isoforms IX and XII compared to II, which correlates with experimental data. Our results may explain why levetiracetam is also clinically effective as an antitumor agent in patients developing epilepsy as a consequence of brain tumors.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2133–2139 2133–2139"},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11eCollection Date: 2024-12-12DOI: 10.1021/acsmedchemlett.4c00521
Robert B Kargbo
Psychedelic compounds, particularly psilocybin and psilocin, have shown significant therapeutic potential in treating neurological and psychiatric disorders. However, their bioavailability, rapid metabolism, and stability challenges have limited their clinical use. This Patent Highlight reviews recent innovations in psychedelic drug delivery systems and the development of psilocin analogs aimed at improving their pharmacokinetic and pharmacodynamic profiles. Three patents-focused on controlled-release delivery systems, ester analogs, and acetal/ketal derivatives-present novel approaches to enhancing the stability, bioavailability, and efficacy of psilocin and related compounds. These advancements promise more effective treatments for conditions such as depression, chronic pain, and neurodegenerative diseases.
{"title":"Advanced Delivery Systems and Novel Psilocin Derivatives for Enhanced Therapeutic Applications.","authors":"Robert B Kargbo","doi":"10.1021/acsmedchemlett.4c00521","DOIUrl":"10.1021/acsmedchemlett.4c00521","url":null,"abstract":"<p><p>Psychedelic compounds, particularly psilocybin and psilocin, have shown significant therapeutic potential in treating neurological and psychiatric disorders. However, their bioavailability, rapid metabolism, and stability challenges have limited their clinical use. This Patent Highlight reviews recent innovations in psychedelic drug delivery systems and the development of psilocin analogs aimed at improving their pharmacokinetic and pharmacodynamic profiles. Three patents-focused on controlled-release delivery systems, ester analogs, and acetal/ketal derivatives-present novel approaches to enhancing the stability, bioavailability, and efficacy of psilocin and related compounds. These advancements promise more effective treatments for conditions such as depression, chronic pain, and neurodegenerative diseases.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2080-2082"},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1021/acsmedchemlett.4c0052010.1021/acsmedchemlett.4c00520
Robert B. Kargbo*,
Recent advancements in cancer therapy have led to groundbreaking approaches targeting critical oncogenic pathways. This Patent Highlight explores four essential patents that focus on modulating ligand–receptor interactions from placental immunology, degrading RAF proteins with MEK1/2 degraders, and employing PROTAC technology to degrade Cyclin D, CDK4, and CDK6 proteins. These innovations aim to overcome traditional therapy limitations and address resistance in cancers such as breast, lung, and RAS-altered cancers. This publication examines these inventions’ mechanisms, findings, and implications in modern cancer treatment.
{"title":"Innovative Cancer Therapies: Targeting Oncogenic Pathways through Placental Immunology, PROTAC Technology, and Kinase Degradation","authors":"Robert B. Kargbo*, ","doi":"10.1021/acsmedchemlett.4c0052010.1021/acsmedchemlett.4c00520","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00520https://doi.org/10.1021/acsmedchemlett.4c00520","url":null,"abstract":"<p >Recent advancements in cancer therapy have led to groundbreaking approaches targeting critical oncogenic pathways. This Patent Highlight explores four essential patents that focus on modulating ligand–receptor interactions from placental immunology, degrading RAF proteins with MEK1/2 degraders, and employing PROTAC technology to degrade Cyclin D, CDK4, and CDK6 proteins. These innovations aim to overcome traditional therapy limitations and address resistance in cancers such as breast, lung, and RAS-altered cancers. This publication examines these inventions’ mechanisms, findings, and implications in modern cancer treatment.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2077–2079 2077–2079"},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09eCollection Date: 2025-01-09DOI: 10.1021/acsmedchemlett.4c00452
Mathieu Joyal, Ryan D Simard, Wael Maharsy, Michel Prévost, Mona Nemer, Yvan Guindon
Inflammatory disorders, such as sepsis, pancreatitis, and severe COVID-19, often cause immune dysfunction and high mortality. These conditions trigger excessive immune cell influx, leading to cytokine storms, organ damage, and compensatory immune suppression that results in immunoparalysis, organ dysfunction, and reinfection. Controlled and reversible immunosuppression limiting immune cell recruitment to inflammation sites could reduce hyperinflammation and prevent immune exhaustion. PSGL-1 on leukocytes binds to vascular P- and E-selectins via its sialyl Lewisx pharmacophore, triggering key features of systemic inflammatory response syndrome and sepsis. We report the discovery of two immunomodulators, sialyl Lewisx glycomimetics (12 and 13), with a tetrazole carboxyl bioisostere of 3a, which binds P- and E-selectin and blocks their interaction with PSGL-1. In an in vivo hyperinflammation model, they reduced immune cell recruitment, evidenced by decreased neutrophils, CD11b+, monocytes/macrophages, and PSGL-1-positive cells at various time points. These glycomimetics may be promising leads for managing the systemic inflammatory response syndrome.
{"title":"Sialyl Lewis<sup>x</sup> Glycomimetics as E- and P-Selectin Antagonists Targeting Hyperinflammation.","authors":"Mathieu Joyal, Ryan D Simard, Wael Maharsy, Michel Prévost, Mona Nemer, Yvan Guindon","doi":"10.1021/acsmedchemlett.4c00452","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00452","url":null,"abstract":"<p><p>Inflammatory disorders, such as sepsis, pancreatitis, and severe COVID-19, often cause immune dysfunction and high mortality. These conditions trigger excessive immune cell influx, leading to cytokine storms, organ damage, and compensatory immune suppression that results in immunoparalysis, organ dysfunction, and reinfection. Controlled and reversible immunosuppression limiting immune cell recruitment to inflammation sites could reduce hyperinflammation and prevent immune exhaustion. PSGL-1 on leukocytes binds to vascular P- and E-selectins via its sialyl Lewis<sup>x</sup> pharmacophore, triggering key features of systemic inflammatory response syndrome and sepsis. We report the discovery of two immunomodulators, sialyl Lewis<sup>x</sup> glycomimetics (<b>12</b> and <b>13</b>), with a tetrazole carboxyl bioisostere of <b>3a</b>, which binds P- and E-selectin and blocks their interaction with PSGL-1. In an <i>in vivo</i> hyperinflammation model, they reduced immune cell recruitment, evidenced by decreased neutrophils, CD11b+, monocytes/macrophages, and PSGL-1-positive cells at various time points. These glycomimetics may be promising leads for managing the systemic inflammatory response syndrome.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 1","pages":"64-71"},"PeriodicalIF":3.5,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1021/acsmedchemlett.4c0052310.1021/acsmedchemlett.4c00523
Ram W. Sabnis*,
Provided herein are novel pyridazine compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating Parkinson’s disease or frontotemporal dementia, and processes for preparing such compounds.
{"title":"Pyridazine Compounds as NLRP3 Inhibitors for Treating Parkinson’s Disease or Frontotemporal Dementia","authors":"Ram W. Sabnis*, ","doi":"10.1021/acsmedchemlett.4c0052310.1021/acsmedchemlett.4c00523","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00523https://doi.org/10.1021/acsmedchemlett.4c00523","url":null,"abstract":"<p >Provided herein are novel pyridazine compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating Parkinson’s disease or frontotemporal dementia, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2083–2084 2083–2084"},"PeriodicalIF":3.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142844140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07eCollection Date: 2024-12-12DOI: 10.1021/acsmedchemlett.4c00523
Ram W Sabnis
Provided herein are novel pyridazine compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating Parkinson's disease or frontotemporal dementia, and processes for preparing such compounds.
{"title":"Pyridazine Compounds as NLRP3 Inhibitors for Treating Parkinson's Disease or Frontotemporal Dementia.","authors":"Ram W Sabnis","doi":"10.1021/acsmedchemlett.4c00523","DOIUrl":"10.1021/acsmedchemlett.4c00523","url":null,"abstract":"<p><p>Provided herein are novel pyridazine compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating Parkinson's disease or frontotemporal dementia, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2083-2084"},"PeriodicalIF":3.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1021/acsmedchemlett.4c0040110.1021/acsmedchemlett.4c00401
Ross P. Hryczanek*, Andrew S. Hackett, Paul Rowland, Chun-wa Chung, Máire A. Convery, Duncan S. Holmes, Jonathan P. Hutchinson, Semra Kitchen, Justyna Korczynska, Robert P. Law, Jonathan D. Lea, John Liddle, Richard Lonsdale, Margarete Neu, Leng Nickels, Alex Phillipou, James E. Rowedder, Jessica L. Schneck, Paul Scott-Stevens, Hester Sheehan, Chloe L. Tayler, Ioannis Temponeras, Christopher P. Tinworth, Ann L. Walker, Justyna Wojno-Picon, Robert J. Young, David M. Lindsay and Efstratios Stratikos,
Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the N-terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease. Herein we describe the hit-to-lead optimization of a series of cyclohexyl acid ERAP1 inhibitors, found by X-ray crystallography to bind at an allosteric regulatory site. Structure-based drug design enabled a >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound 7, rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization.
{"title":"Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design","authors":"Ross P. Hryczanek*, Andrew S. Hackett, Paul Rowland, Chun-wa Chung, Máire A. Convery, Duncan S. Holmes, Jonathan P. Hutchinson, Semra Kitchen, Justyna Korczynska, Robert P. Law, Jonathan D. Lea, John Liddle, Richard Lonsdale, Margarete Neu, Leng Nickels, Alex Phillipou, James E. Rowedder, Jessica L. Schneck, Paul Scott-Stevens, Hester Sheehan, Chloe L. Tayler, Ioannis Temponeras, Christopher P. Tinworth, Ann L. Walker, Justyna Wojno-Picon, Robert J. Young, David M. Lindsay and Efstratios Stratikos, ","doi":"10.1021/acsmedchemlett.4c0040110.1021/acsmedchemlett.4c00401","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00401https://doi.org/10.1021/acsmedchemlett.4c00401","url":null,"abstract":"<p >Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the <i>N</i>-terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease. Herein we describe the hit-to-lead optimization of a series of cyclohexyl acid ERAP1 inhibitors, found by X-ray crystallography to bind at an allosteric regulatory site. Structure-based drug design enabled a >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound <b>7</b>, rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2107–2114 2107–2114"},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142844108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}